Preparation for the relief of disease

ABSTRACT

A composition including (a) a Platelet Activating Factor (PAF) Inhibitor and (b) an antioxidant which interferes with the arachidonic acid cascade and also has antioxidant activity. The compositions are useful for the treatment or the relief of inflammatory disease, thrombosis, cardiac problems, and/or conditions caused by platelet induced blood clotting.

[0001] The present invention relates to preparations for the treatmentor relief of diseases, especially inflammatory diseases, in humans andanimals. in particular it relates to preparations for the treatment ofinflammatory respiratory diseases such as asthma in humans, especiallyin children.

[0002] Asthma is a chronic disease of the airways characterised byrecurrent airway obstruction. Known treatments of asthma include dailydoses of pharmaceuticals such as inhaled corticosteroids, antihistaminesand inhaled beta agonist bronchodilators such as Ventolin (RTM). The aimof such treatments is to manage or ameliorate the condition, that is toprovide symptomatic relief of wheezing and/or breathlessness and/orcoughing. Unfortunately, even with such treatments, asthma sufferers areprone to severe asthma attacks or crises which may be brought on orexacerbated by other illness such as colds or influenza, allergens (forexample pollen, house dust etc.) or by exercise. Such crisis points mayinvolve unremitting coughing and other respiratory distress, and maynecessitate hospitalisation and/or out patient emergency care toadminister repeated bronchodilation therapy, oxygen therapy, and highdoses of oral glucocorticosteroids.

[0003] A major goal of asthma therapy is the prevention of crises whichrequire emergency therapy and or/oral corticosteroid treatment. This isfor two major reasons. First, it is the crises which are the major causeof the morbidity and mortality associated with asthma. Secondly,recurrent steroid use, especially at high doses of oral steroids, isassociated with multiple adverse affects, which are well documented.

[0004] Inhalation therapy of asthma using an inhaler is the standardtreatment for attacks other than severe acute attacks, but has severaldisadvantages. It requires co-ordination of discharge of the inhalerwith inhalation, which many people, especially children, find difficult.It also requires considerable respiratory effort which those sufferingfrom asthma find difficult.

[0005] Beta 2 bronchodilators, e.g. salbutamol (Ventolin) andterbutaline (Bricanyl) are usually taken by inhalation, but may be takenorally. When taken orally, these compounds have considerable adverseeffects, such as inducing tremor and/or cardiovascular side effects(such adverse effects can also follow inhalation administration but areless likely). The side effects are particularly bad at high doses. Oralsteroids e.g. prednisolone and prednisone, which are used in acuteasthma attacks, also have known (and considerable) side effects; thesecompounds are generally taken for a short period in order to alleviatethe attack while avoiding those side effects.

[0006] Thus, known oral treatments for asthma either suffer from thesevere and well known side effects associated with glucocorticosteroids,or have not proved very effective. There is therefore a considerableneed for an effective oral treatment for asthma and other respiratorydiseases.

[0007] According to the present invention there is provided acomposition including (a) a Platelet Activating Factor (PAF) Inhibitorand (b) an antioxidant which interferes with the arachidonic acidcascade. Preferably, the antioxidant (b) is an NADPH oxide inhibitor.Preferably, the antioxidant (b) increases glutathione synthesis.Antioxidant (b) is preferably a neutrophil oxidative burst antagonist.

[0008] Platelet-activating factor (PAF) is an ether-linked phospholipid(acetyl glycerol ether phosphocholine) produced by many different kindsof stimulated cells (e.g., basophils, neutrophils, monocytes,macrophages, endothelial cells) from phospholipids which are mobilizedfrom cell membranes by phospholipase A2. It is 100-to-10,000 times morepotent than histamine with respect to its vasoactive properties. As oneof its smooth muscle effects, it is a strong bronchoconstrictor. It alsostimulates other cells to increase their functional and metabolicactivities, i.e., primes or activates them for more effective function.It is a potent platelet-aggregating agent and inducer of systemicanaphylactic symptoms.

[0009] PAF inhibitor should be taken to mean an agent which inhibits PAFby any mechanism.

[0010] Preferably the Platelet Activating Factor (PAF) Inhibitor (a) isa a gingkolide. Preferably the source of gingkolide(s) is gingko biloba,or extract or component thereof.

[0011] Ginkgolides, for examlple, ginkgolide B are display potent (PAF)inhibiting activity. This may-lead to reduction of bronchoconstriction,induction of airways hyperactivity and eosinophil response.

[0012] The structure of gingkolide B (Molecular Formula: C₂₀ H₂₄ O₁₀) isshown below.

[0013] The gingkolides are bioactive terpenes isolated from the roots,bark and/or. leaves of Ginkgo biloba L., Ginkgoaceae. Other sutablegingkolides are those compounds which can be extracted from, forexample, the roots, bark and/or leaves of Ginkgo biloba L., Ginkgoaceaeby a polar organic solvent.

[0014] Arachidonic acid (AA) is the substrate from which eicosanoids,e.g., prostaglandins, leukotrienes, and numerous other mediators, areproduced. Eicosanoids can collectively mediate almost every aspect ofthe inflammatory response. AA is produced from membrane phospholipidsand fatty acids through the effects of various phospholipases. AA is notstored in cells, however, it is produced and metabolized into mediatorsvery rapidly. The process by which eicosanoids is made (from AA) istermed the arachidonic acid AA cascade, and is well known. The mainmediating enzymes in the AA cascade are of the cyclooxygenase. class,enzymes principally inhibited by aspirin and other NSAIDS, as well asCOX-2 inhibitors.

[0015] By “an antioxidant which interferes with arachidonic acidcascade” it is meant any antioxidant that affects any stage of the AAcascade (for example by inhibition of a mediating enzyme). Theantioxidant may be said to have two modes of action: (i) an antioxidantaction; and (ii) an action which affects the AA cascade.

[0016] Preferably, the antioxidant (b) is apocynin. This may be inisolated form (e.g. apocynin), a precursor, for example the dimer, theGlucoside (for example androsin), glycone or in the form ofacetovanillone), and/or apocynin in natural form (e.g in the form ofpicrorrhiza kurroa). These forms are discussed in more detail below.

[0017] The compositions, preparations and and methods according to theinvention are useful as (or in the manufacture of) pharmaceuticalpreparations for the treatment of human patients, and/or as (or in themanufacture of) veterinary preparations for the treatment of non humananimals, because they demonstrate activity as discussed below and shownin test data (see, for example, Example 13). The tests indicate that thecomposition(s) and/or preparation(s) are suitable for use in thetreatment or amelioration or relief of inflammatory disease. Preferably,they are used for the treatment or amelioration or relief ofinflammatory respiratory disease. “Inflammatory respiratory disease”includes respiratory diseases such as asthma, allergic airways diseaseand emphysema (e.g. hereditary emphysema), symptoms of allergymanifested in the respiratory system, exercise induced asthma andChronic Obstructive Pulmonary Disease (COPD) (bronchitis). Thepreparation may also be used to treat inflammatory diseases such asinflammatory joint disease, arthritis and rheumatoid osteoarthritis,(atopic) dermatitis, leishmaniasis and/or inflammatory diseases of thegastrointestinal tract, such as ulcers (including stomach ulcers),gastric ulcer syndrome, ulcerative collitis, coeliac disease, IrritableBowel syndrome, Irritable Bowel Disease and Crohn's disease. Thepreparations may also be used to prevent Platelet Induced bloodclotting, and thus are suitable for use in the treatment, managementand/or prevention of conditions caused by Pletelet Induced bloodclotting (for example Coronary Artery Disease, Arterial Clotting, PAD(peripheral arterial disease and Stroke). The preparations andcompositions may also be used in the treatment, management and/orprevention of thrombosis and cardiac related problems (for exampleischaemia and blood flow problems, arrhythmias induced by experimentalmyocardial ischaemia, prevention or reduction of arteriolar spasm andproblems caused by thrombus formation).

[0018] The compositions and preparations may be used to treat, manage,or prevent hayfever (allergic rhinitis). Preferred compositions for thisuse further comprise dimethyl sulfone.

[0019] The compositions may be used as (or in the manufacture of)veterinary preparations for the treatment of non human animals, forexample dogs, pigs, equine species, poultry and reared game birds suchas pheasants. They may be used to treat inflammatory diseases such asseasonal pruritic dermatitis, laminitis, ecezmatous . dermatitis, COPD,lameness, azoturia, dermatitis, rain scald, osteoathritis, hip dysplasiaand leishamaniasis, equine gastroulcer syndrome, or the sequellaethereof.

[0020] The combination of pharmaceutically significant amounts of activeingredients, antioxidant (b) (e.g. apocynin) and PAF Inhibitor (e.g.ginkgo biloba), may have a synergistic effect that leads to extremelyefficaceous treatment of diseases, for example asthma. Treatment usingpreparations of the invention may lead to considerable benefits ingeneral health, such as up to a 95% reduction in symptoms of asthma andother more general manifestations, such as increased wellness andhappiness, colour (indicative of improved oxygenation), and, inchildren,. apparent increased growth and development. There may also bea significant reduction in the amount of crises and thus a decreasedneed for hospital or out-patient treatment.

[0021] “Treatment using preparations of the invention” should be takento mean both administration of the preparation at a preventative ormaintenance dose with the aim of prophylaxis (that is preventing or atleast reducing the frequency of attacks and therefore maintaining alevel of health, and/or preventing the development of a condition), andtreatment at a (generally higher) “therapeutic level” to alleviatechronic attacks or crisis symptoms which if untreated may lead tohospitalisation. Thus the preparation may remove or reduce the need fortreatments considered harmful such as corticosteroids, especially oralcorticosteroid treatments. However, the preparations/compositions may beadministered in combination with conventional asthma treatments(Ventolin, oxygen therapy, corticosteroids, breathing techniques etc)without ill effects, and may enable the dose of conventional treatmentto be reduced (dose sparing).

[0022] Examples of compositions suitable for use as antioxidant (b) areNADPH-oxidase inhibitors such as catechols and their metabolites andmethylated catechols, for example apocynin.

[0023] Preferably, the antioxidant (b) is apocynin which is theplant-phenol 4-hydroxy-3-methoxyacetophenone, and has the followingformula:

[0024] Apocynin interferes with arachidonic acid cascade, increasesglutathione synthesis, and is a neutrophil oxidative burst antagonist.These effects may contribute to the increased therapeutic effects shownby preparations including apocynin.

[0025] The antioxidant (b) may also be an apocynin derivative or aphenone derivative. Some examples of suitable phenone derivatives aredisclosed in U.S. Pat. No. 5,481,043.

[0026] NADPH-oxidase inhibitors (suitable for use as antioxidant (b))may be found in plant substances and plant extracts. For example,apocynin is found in extracts of the plants picrorrhiza kurroa, apocynumcannabinium, apocynum venatum or apocynum androsaemifolium. Thepreparations of the invention may include an “isolated” NADPH-oxidaseinhibitor (for example “isolated” apocynin). Isolated NADPH-oxidaseinhibitor is an NADPH-oxidase inhibitor which has been synthesised, orNADPH-oxidase inhibitor which has been extracted from plants andpurified. Apocynin (or other NADPH-oxidase inhibitors) may be present inpreparations according to the invention as direct extracts from plants(i.e. as part of an unresolved mixture of compounds in the form of anunpurified plant or root extract). These will be referred to asNADPH-oxidase inhibitors (or apocynin) “in the natural form”. Forexample, apocynin present in preparations according to the invention inthe form of picrorrhiza kurroa will be referred to as “naturalapocynin”. Natural apocynin may include androsin and other iridoidglucosides, for example.

[0027] Preferably the composition includes antioxidant (b) which is anNADPH-oxidase inhibitor in a purified or synthetic form: “isolated”NADPH-oxidase inhibitor.

[0028] It is a still further preference that the antioxidant (b) whichis an NADPH-oxidase inhibitor is present in both isolated form and anatural form.

[0029] As discussed above the preferred antioxidant (b) is apocynin. Ifapocynin is used in the preparation in “isolated form” it is a furtherpreference that the preparation also comprises a natural form ofapocynin, for example from an apocynin containing plant such aspicrorrhiza kurroa, apocynum cannabinium, apocynum venatum or apocynumandrosaemifolium, most preferably an extract from picrorrhiza kurroa.The use of active entity in the natural form in combination with the“isolated” active entity may lead to a further synergistic effectbetween the isolated form (e.g. purified or synthetic apocynin)and thenatural form (e.g. apocynin contained in picrorrhiza kurroa). Thepreferred picrorrhiza kurroa is a standardised form based onstandardised iridoid glucoside fractions such as are well known. APreferred picrorrhiza kurroa in standardised form comprises standardisediridoid glucoside fractions collectively known as “Kutkin min 4%”.Standardised iridoid glucoside fractions between Kutkin min 2% andKutkin min 8% are also preferred. In the Examples below, the picrorrhizakurroa in standardised form comprises standardised iridoid glucosidefractions collectively known as “Kutkin min 2%”.

[0030] The composition may include antioxidant (b) which is anNADPH-oxidase inhibitor in natural form only, for example picrorrhizakurroa. However, if this is the case it may be necessary to limit theamount of picrorrhiza kurroa to orevent side effects (such as stomachupset which may occur due to other species in the picrorrhiza kurroa).However, it is noted that most human subjects can take upto 2,000 mg ofpicrorrhiza kurroa (Kutkin min 2%)per day without discomfort.

[0031] A preferred composition comprises:

[0032] a) gingko biloba; and

[0033] b) antioxidant, preferably NADPH-oxidase inhibitor, preferablyapocynin;

[0034] wherein the ratio by weight of gingko biloba :antioxidant isbetween about 3:10 and about 3.4:1, preferably between about 0.5:1 andabout 3:1, and more preferably between about 2.1:1 and 2.7:1.

[0035] In the ratio above the weight of antioxidant refers to the weightin the isolated form (e.g. apocynin in the isolated form).

[0036] Thus, according to the invention in another aspect there isprovided a pharmaceutical preparation for the treatment or relief ofinflammatory disease, thrombosis, cardiac problems and/or conditionscaused by Platelet Induced blood clotting comprising (a) a PlateletActivating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade. Preferably, theantioxidant (b) is an NADPH oxide inhibitor. Preferably, the antioxidant(b) increases glutathione synthesis. Antioxidant (b) is preferably aneutrophil oxidative burst antagonist.

[0037] Preferably the Platelet Activating Factor (PAF) Inhibitor isgingko biloba. Preferably the antioxidant (b) is apocynin.

[0038] The apocynin may be in isolated form. Preferably, the preparationfurther comprises apocynin in the natural form. Preferably thepreparation is a pharmaceutical preparation for the treatment ofinflammatory disease in the human. Preferably, the preparation is forthe treatment of inflammatory respiratory disease.

[0039] A preferred pharmaceutical preparation inflammatory diseasecomprises:

[0040] a) gingko biloba; and

[0041] b) antioxidant, preferably NADPH-oxidase inhibitor, preferablyapocynin;

[0042] wherein the ratio by weight of gingko biloba antioxidant isbetween about 3:10 and about 60:1, preferably between about 6:1 andabout 0.4:1, more preferably between about 2.4:1 and about 0.45:1, evenmore preferably between about 2.1:1 and about 1.4:1.

[0043] In the ratio above the weight of antioxidant refers to the weightin the isolated form (e.g. apocynin in the isolated form).

[0044] The preparations and compositions in the preceding paragraphsassume the gingko biloba is in natural form. Preferably the ginkgobiloba is in concentrated standard form, for example a concentratedextract which is equivalent to four times the concentration of gingkobiloba in the natural form, such as Gingko biloba tablets sold byMediHerb of Australia (500 mg tablets containing gingko bilobaconcentrated extract equivalent to 2.0 g dry leaf gingko bilobastandardised to Gingko flavone glycosides). Thus, a preferredpreparation which includes gingko biloba in such a concentrated standardform comprises:

[0045] a) gingko biloba (in concentrated standard form);

[0046] b) antioxidant, preferably NADPH-oxidase inhibitor, preferablyapocynin;

[0047] wherein the ratio by weight gingko biloba: antioxidant is betweenabout 30:1 and about 75:1000, preferably between about 3:1 and about1:1, more preferably about 3:2.

[0048] It is noted that in preparations according to the invention alevel of antioxidant (b) (such as NADPH-oxidase inhibitor, for example.apocynin) higher than the minimum value specified above makes thepreparation more suitable for a therapeutic treatment, while a amount ofantioxidant (b) of around the minimum value noted above makes thepreparation more suitable for a standard preventative measure treatment.

[0049] Preferably, the composition (or preparation) further comprises anagent which enhances lipid solubility of the preparation. This givesrise to better absorption and hence better bioavailability, especaillyby the oral route. Preferred agents which enhances lipid solubility aresources of pharmaceutically acceptable surfactants and/or fatty acids,for example phosphatidylcholine (lecithin).

[0050] Preferably, the compositions or preparations further comprisedimethyl sulfone. Such preparations are especially suitable for treatinghayfever (allergic rhinitis).

[0051] The preparation may further comprise additional components suchas pharmaceutically conventional carriers, diluents, flavourants,emulsifiers and stabilisers. Preferably the preparation furthercomprises one or more of of the following:

[0052] i) an agent to enhance the immune system, for example lactoferrinwhich has anti-viral, antibacterial and anti-oxidant effects;

[0053] ii) a natural source of vitamins or minerals such as bee pollen;

[0054] iii) a source, for example a natural source, of vitamins,minerals and amino acids, for example chlorella;

[0055] iv)a source of trace elements, for example fucus vesiculosus;and/or

[0056] v)Taste masking agents, for example yoghurt, fruit juice, honeyand syrup.

[0057] The compositions and preparations are suitable for oraladministration. Thus, in another aspect the present invention providesan orally bioavailable preparation for the treatment or relief ofinflammatory disease, thrombosis, cardiac problems and/or conditionscaused by Platelet Induced blood clotting comprising (a) a PlateletActivating Factor (PAF) Inhibitor and (b)antioxidant which interfereswith the arachidonic acid. Preferably, the antioxidant (b) is anNADPH.oxide inhibitor. Preferably, the antioxidant (b) increasesglutathione synthesis. Antioxidant (b) is preferably a neutrophiloxidative burst antagonist.

[0058] Preferably the Platelet Activating Factor (PAF) Inhibitor (a) isgingko biloba. Preferably the antioxidant (b) is apocynin.

[0059] In a still further aspect, the present invention provides anorally bioavailable preparation for the treatment of inflammatoryrespiratory disease comprising gingko biloba and apocynin. The apocyninmay be in isolated form (e.g. apocynin as the dimer, glycone or in theform of acetovanillone) or in natural form (e.g in the form ofpicrorrhiza kurroa). Preferably the apocynin is present in natural andisolated forms.

[0060] Thus, the invention may provide an orally active anti-asthmaticpreparation. It will be appreciated that the preparations are suitablefor other means of administration, for example mucosal delivery routes(for example rectal, nasal, vaginal) and also topical administration.

[0061] According to the present invention there is also provided amethod of treatment or relief of inflammatory disease, thrombosis,cardiac problems and/or conditions caused by Platelet Induced bloodclotting in human or other animal subject comprising the step(s) ofadministering to the subject (a) a Platelet Activating Factor (PAF)Inhibitor and (b) an antioxidant which interferes with the arachidonicacid cascade.

[0062] Preferably, the antioxidant (b) is an NADPH oxide inhibitor.Preferably, the antioxidant (b) increases glutathione synthesis.Antioxidant (b) is preferably a neutrophil oxidative burst antagonist.The present invention also provides a method comprising use of (a) aPlatelet Activating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade in the manufacture of amedicament for the treatment of inflammatory disease in human or otheranimal.

[0063] Preferably, the method is for the treatment (and/or ameliorationor relief) of inflammatory respiratory diseases, for example thosediscussed in paragraphs above, for example, asthma, allergic airwaysdisease and emphysema. (for example hereditary emphysema), hayfever,allergic rhinitis, symptoms of allergy manifested in the respiratorysystem, exercise induced asthma and Chronic Obstructive PulmonaryDisease (COPD) (bronchitis). The method may also be used to treatinflammatory disease such as inflammatory joint disease, arthritis andrheumatoid osteoarthritis, and/or inflammatory diseases of thegastrointestinal tract, such as ulcerative collitis, coeliac disease,Irritable Bowel syndrome, Irritable Bowel Disease and Crohn's disease.The method may be used to prevet platelet induced blood clotting,thrombosis, cardiac problems and other conditions discussed above.

[0064] Preferably, the Platelet Activating Factor (PAF) Inhibitor isgingko biloba. Preferably, the preparation is administered to a human ata concentration, per daily dose, of gingko biloba (standardised togingko flavone glycosides—24%) of 1 mg/kg body weight—25 mg/kg bodyweight.

[0065] Preferably the antioxidant (b) is apocynin. Preferably, thepreparation is administered to a human at a concentration, per dailydose, of apocynin of 60 μg/kg body weight—20 mg/kg body weight.

[0066] Preferably the method further comprises the step of administeringa natural form of antioxidant (b), as described above, for examplepicrorrhiza kurroa. Preferably, the preparation is administered at aconcentration, per daily dose, of picrorrhiza kurroa of 1 mg/kg bodyweight—35 mg/kg body weight. This preferred daily dose of picrorrhizakurroa is based on standardised iridoid glucoside fractions collectivelyknown as “Kutkin min 4%”.

[0067] The above ranges are a maintenance dose (for prophylactictreatment) for a human patient. For a loading dose (e.g. to begintreatment or treat an acute attack) the daily dose should be doubled fora period of 1 -5, preferably 3 days.

[0068] There may be a cumulative effect which provides clinical benefitsover a longer period, of 10 to 30 days.

[0069] The daily dose may be provided as a single capsule, tablet orother solid or liquid form known to those skilled in the art, or may beprovided in divided doses (for example 1 to 3 doses) to make up the fulldaily dose. The doses of gingko biloba and antioxidant (b), for exampleapocynin, may be provided together in the capsule, tablet etc, or thetwo may be provided as separate capsules or tablets (a capsulecontaining dose or partial dose of gingko biloba, and a separate capsulecontaining the antioxidant (b), for example apocynin) for sequentialadministration.

[0070] The following are preferred compositions/doses for the treatmentof animals. The preferred Platelet Activating Factor (PAF) Inhibitor isgingko biloba. Preferably the antioxidant (b) is apocynin. Preferablythe method further comprises the step of administering a natural form ofantioxidant (b), as described above, for example picrorrhiza kurroa.

[0071] For dogs, the preferred doses are a concentration, per dailydose, of gingko biloba (standardised to gingko flavone glycosides—24%)of 1 mg/kg body weight—7 mg/kg body weight; a concentration, per dailydose, of apocynin of 0.6 mg/kg body weight—35 mg/kg body weight. Thedose may also comprise a daily dose of picrorrhiza kurroa of 3 mg/kgbody weight—6.6 mg/kg body weight. The preferred daily dose ofpicrorrhiza kurroa is based on standardised iridoid glucoside fractionscollectively known as “Kutkin min 4%”.

[0072] For horses, the preferred doses are a concentration, per dailydose, of gingko biloba (standardised to gingko flavone glycosides—24%)of 4 mg/kg body weight—23 mg/kg body weight; a concentration, per dailydose, of apocynin of 0.2 mg/kg body weight—1.1 mg/kg body weight. Thedose may aso comprise and a daily dose of picrorrhiza kurroa of 1 mg/kgbody weight—5.6 mg/kg body weight. The preferred daily dose ofpicrorrhiza kurroa is based on standardised iridoid glucoside fractionscollectively known as “Kutkin min 4%”.

[0073] According to the present invention in a further aspect, there isprovided a kit of parts for a preparation for treatment or prevention ofinflammatory disease, thrombosis, cardiac problems and/or conditionscaused by Platelet Induced blood clotting in human or other animalsubject comprising at least one dose of (a) a Platelet Activating Factor(PAF) Inhibitor and (b) an antioxidant which interferes with thearachidonic acid cascade. Preferably the Platelet Activating Factor(PAF) Inhibitor is gingko biloba. Preferably the antioxidant (b) isapocynin.

[0074] It is envisaged that the kit of parts may be provided as, forexample, a blister pack containing capsules containing doses or partialdoses of, for example, gingko biloba, and separate capsules containingdoses or partial doses of the antioxidant (b) (e.g apocynin). The packmay be provided with instructions for sequential administration of thedoses.

[0075] When administered either together or separately the compounds (a)and (b) should be such as to maintain a suitable blood level of each of(a) and (b). When administered separately the compounds (a) and (b)should be given within four hours of each other, preferably within twohours, and more preferably simultaneously.

[0076] Preferably the inflammatory disease is inflammatory respiratorydisease, for example asthma. The disease may be allergenic in nature.

[0077] It is preferred that the preparation is administered orally, forexample in pill or capsule form, although it is possible to use otherknown conventional administration techniques.

[0078] The compositions (and preparations) of the invention may be usedas a sole treatment. They may also be used alongside conventionalmedicines (e.g. anti-allergics such as steroids and antihistamines whichhave unwanted side effects); this may lead to a reduction in the dose ofconventional medicine required and thus a reduction inlikelihood/occurunce of the side effects. A reduction of side effects ofa therapeutic agent (for example the side effects of anti-allergicagents) during treatment of human or animal patients being treated isknown as “dose sparing”.

[0079] Thus, according to the invention in a still further aspect thereis provided a method of dose sparing a therapeutic agent comprising thestep of administering to the patient a preparation comprising (a) aPlatelet Activating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade. Preferably the PlateletActivating Factor (PAF) Inhibitor is gingko biloba. Preferably theantioxidant (b) is apocynin. The preparation may be administered at thesame time as the therapeutic agent (for example the anti-allergic agent)or at a different time, by the same administration route, or by adifferent administration route.

[0080] The examples and description relate (in places) to asthma but itwill be understood that the preparations of the invention are suitablefor treatment or amelioration or prevention of other diseases,especially other inflammatory diseases, as discussed above. These maybe, for example, other respiratory inflammatory diseases such asemphysema. It will also be understood that, amongst other things, thepreparations of the invention are suitable for treatment or diminuitionof the symptoms of allergic attacks or allergic reactions such as insectbites or stings. The preparations of the invention are suitable fortreatment, amelioration or prevention of inflammatory gastrointestinaltract disorders. The preparations of the invention are suitable fortreatment or prevention of inflammatory disease, e.g. inflammatoryrespiratory disease in animals, for example dogs and horses.

DETAILED DESCRIPTION OF THE INVENTION

[0081] Embodiments of the present invention will now be exemplified, andillustrated with reference to the attached Figures, in which:

[0082]FIG. 1 shows the effect of Extracts 2, 5 and 8 alone or incombination on maximum platelet aggregation in response to ADP 4×10⁻⁶M(Example 13);

[0083]FIG. 2 shows the platelet aggregation response to ADP 4×10⁻⁶M insamples treated with 1) control; 2) 6 μl extract 2; 3) 6 μl extract 5;and 4) 6 μl extract 8(Example 13); and

[0084]FIG. 3 shows the platelet aggregation response to ADP 4×10⁻⁶M insamples treated with 1) 3 μl extract 2 and 3 μl extract 5; 2) 3 μlextract 2 and 3 μl extract 8; 3) 3 μl extract 5 and 3 μl extract 8; and4) 2 μl extract 2 and 2 μl extract 5 and 2 μl extract 8 (Example 13)

EXAMPLE PREPARATIONS Example 1

[0085] The following reagents were mixed: apocynin 100 mg picorrhizakurroa 200 mg lactoferrin 60 mg ginkgo biloba** 150 mg bee pollen 120 mgchlorella pyrenoidosa 250 mg phophatidylcholine (lecithin) 100 mg fucusvesiculosus 20 mg

[0086] The lactoferrin, bee pollen, chlorella pyrenoidosa,phophatidylcholine (lecithin) and fucus vesiculosus serve as thevehicle.

[0087] ** The ginkgo biloba used was a concentrated extract equivalentdry leaf (that is concentrated at a ratio 1:4) and standardised toginkgo flavone glycosides ˜18%. Thus, for the same concentration, 600 mgof “natural” ginkgo biloba would be used.

[0088] The mixture was divided and prepared in form suitable for dosing,for example in capsule form for oral dose.

EXAMPLE 1 A

[0089] The following compounds were mixed and used for adults and largerchildren: apocynin 180 g picrorrhiza kurroa 360 g gingko biloba** 260 gchlorella pyrenoidosa 100 g phosphatidyl choline (leicithin) 100 g

[0090] 425 mg (size 0 capsules) per 16 kg body weight: splitapproximately twice daily ⅖ dose in the a.m. and ⅗ dose in the p.m.

Example 1 B

[0091] The following compounds were mixed and used for smaller children:apocynin 100 g picrorrhiza kurroa 200 g ginkgo biloba** 150 g bee pollen100 g chlorella pyrenoidosa 280 g phophatidylcholine (lecithin) 150 gfucus vesiculosus 20 g

[0092] 425 mg (size 0 capsules) per 8 kg body weight: split twice daily⅖ dose in the a.m. and ⅗ dose in the p.m. For small children the capsulemay be opened and the contents mixed in fruit yoghurt.

Example 2

[0093] Preventative Treatment of Childhood Asthma

[0094] The subject, now a 10 year old girl, had an initial attack ofbronchial asthma at 4 years old Since then, her condition has beenserious enough to require on numerous occasions immediatehospitalisation and/or out-patient emergency care. Following an asthmacrisis manifested as prolonged unremitting coughing and respiratorydistress over some three days, which necessitated oxygen therapy,repeated broncho dilation therapy and corticosteroids, the subject wasgiven a daily regime of a preparation according to Example 1.

[0095] The dose used was 425 mg of the mixed composition of Example 1per 8 kg body weight (daily dose: 2,125 mg in total) split twice dailywith ⅖ of the dose in the morning and ⅗ in the afternoon. At the end of15 days of treatment, the subject became 80-90% symptom free, with anoverall improvement in general health, activity and general well being.The subject no longer needed a daily dose (either single or combinationdose of corticosteroids, antihistamines and/or bronchodilators; doseswhich had been necessary for five years prior to treatment. No sideeffects or problems were observed or reported.

[0096] Exercise induced asthma still occurred. However, this occurredsignificantly less frequently and was very much more manageable,generally with minimum bronchodilator therapy. The need for such therapywas further reduced by breathing exercises.

[0097] A similar significant response has been observed in childrenbetween the ages of 18 months and 15 years, although it is noted thatwith small children the dose may be administered by breaking open thecapsule and mixing the dose in a more palatable medium, such as fruityoghurt or honey.

[0098] There may not always be an immediate clinical benefit but over aperiod of between 10 to 20 days a general increase in health occurs dueto the cumulative benefits of stabilisation and a return to homeostasis.As with all “preventative therapeutic approaches” there remains theproblem of compliance. If the subject stops taking the preparation areoccurrence of the clinical problems may occur.

[0099] During development of the therapy of Example 2 the synergisticeffect of gingko biloba and apocynin was noted.

Comparison Example 1

[0100] Prior to the mixture of example 1 the subject had been treatedwith gingko biloba alone There was some improvement of the subject'scondition but other medication was still needed; the frequency of use ofmedication (Ventolin inhaler) was reduced during the gingko bilobatherapy from daily to ⅔ times per week.

Comparison Example 2

[0101] As discussed above, the mixture of Example 1 gave a 90%improvement in symptoms with the first subject, and tests generally gavean improvement of 85-95%, i.e. the subject was symptom free 85-95% ofthe time. However, administration of a second mixture omitting thegingko biloba showed an improvement in symptoms reduced to only 60%.Further treatment with the Example 1 mixture for 15 days increased theimprovement to the remarkable 90% symptom free level.

Example 3

[0102] Treatment of Childhood Asthma: Therapeutic Dose

[0103] Example 2 provides a preventative or maintenance dose with theaim of preventing or reducing the frequency of attacks and thereforemaintaining a level of health. The preparation is also suitable fortreatment of the subject at a “therapeutic level” to alleviate crisissymptoms (e.g. prolonged unremitting coughing) which if untreated maylead to hospitalisation. For treatment at a therapeutic level the dailydose is increased by 3-5 times, that is the daily dose is raised to1275-2125 mg/kg body weight. In general, after 3 days at the therapeuticlevel, the crisis symptoms will have been alleviated and the subject'sdose may then be reduced to the maintenance dose of Example 2.

Example 4

[0104] Adult Treatment of Asthma

[0105] An adult male subject reported asthma problems which he hadsuffered for some 6 to 7 years, caused by an allergy to a cat. Thesubject was, prior to treatment according to the invention, prescribedpreventil and vanceril. These inhalers have been used daily by thesubject for the previous 6 years (two puffs of each inhaler twice orthree times daily). Attempts to reduce the medication were problematicand uncomfortable leading to symptoms such as sleeplessness andbreathlessness.

[0106] After administration of the dose and preparation of Example 1 forone week the subject reported feeling “terrific”. The subject alsoreported being able to reduce the frequency of use of preventil andvanceril (reduced to a frequency of one puff a day) without asthmaticflare-up or other side effects.

Example 5

[0107] The subject was a 4 year old boy who had had asthma since the ageof 2, with a history of chronic ongoing asthma on his father's side ofthe family. His asthma was easily provoked by respiratory tractinfections, but less so by environmental allergens. On occasions acuteepisodes had required emergency hospitalisation and emergencymanagement. Previous treatments used salbutamol (Ventolin) and inhaledcorticosteroids (e.g.: Pulmicort/budesonide) as needed. He was treatedwith treated with Example 1B for four months. Clinical examinationsduring subsequent respiratory tract infections have shown no clinicalsigns/manifestations of asthma. Since the start of the treatment therehas been no need for salbutamol or inhaled corticosteroids to controlasthma. Salbutamol has been given, on occasion, during coughing episodesthat occur during the infections, but this was not to control asthma; itappears that the irritant effect from the Salbutamol ‘mist inhalation’provokes a productive sputum cough which resolves the coughing.

Example 6

[0108] The subject was a 70 year old man who had long term chronicobstructive pulmonary disease (COPD) exacerbated by occasional asthma.He had typical pronounced barrel chested appearance and chronicshortness of breath coupled with chronic productive coughing. Previoustreatment was with salbutamol (Ventolin) and inhaled corticosteroids(e.g.: Pulmicort/budesonide) as needed. He was treated with thecomposition of Example 1A and clinical observations at three weeks afterthe initial treatment, and thereafter over a period of 3 months, showeda significant change in facial colouring (blue to red/pink), and minimalproductive sputum coughing. The patient claims to be ‘feeling’ somewhatimproved and insists on continuing the treatment with the composition ofExample 1A. There has been continued clinical improvement with minimumrespiratory discomfort.

[0109] In addition to the chronic obstructive pulmonary disease thepatient suffers from rheumatoid arthritis and since taking thecomposition of Example 1A has observed a significant improvement of thiscondition; he is now able to undertake tasks and journeys on foot thathave not been possible for some years.

Example 7

[0110] The subject was a 13 year old boy who had suffered from asthmasince the age of 5 with a history of chronic ongoing asthma on father'sside of the family. Attacks were easily provoked by respiratory tractinfections and by environmental allergens. On one occasion an acuteongoing episode necessitated emergency hospitalisation for 5 days. Hewas treated with salbutamol (Ventolin) and inhaled corticosteroids(e.g.: Pulmicort/budesonide) as needed. He was treated with thecomposition of Example 1B for 6 months starting after hishospitalisation. After 14 days treatment he showed no further clinicalsigns of asthma and his asymptomatic state continued for the 6 monthperiod during which he took the composition. After ceasing to take thecomposition there was a period of some four weeks before wheezing/asthmaresumed.

Example 8

[0111] The subject was an 8 year old boy having asthma which wasprovoked by intense sport/exercise activity. He was treated withsalbutamol (Ventolin) and inhaled corticosteroids (e.g.:Pulmicort/budesonide) as needed. After a period of hospitalisation hewas given the composition of Example 1B. After 10 days of treatment hedisplayed no clinical signs of asthma during sporting activities.

Example 9

[0112] The subject was a 40 year old woman who had suffered from asthmasince childhood and who was allergic to pollen and animals. Previoustreatments included salbutamol (Ventolin) and inhaled corticosteroids(e.g.: Pulmicort/budesonide). After 28 days taking the composition ofExample 1 all daily inhaled corticosteroids were ceased (such medicationhaving been taken daily for many years) and the patient reported acomplete resolution of her asthma.

Example 10

[0113] The subject was a 40 year old man who had had asthma symptomssince childhood and who was allergic to animals (cats and horses). Hisallergies were exacerbated during summer months indicating a possibleadditional allergy to mixed pollens. He had been treated with Proventiland Vanceril over 6 years (two puffs of each 2 or 3 times per day).After 7 days treatment with the composition of Example 1 his asthmasymptoms had resolved with minimum ‘to be on the safe side’ use ofProventil and Vanceril (1 per day of each). After a further two weekstreatment with the composition he ceased taking the Proventil andVanceril without return of asthma symptoms.

Example 11

[0114] The patient was a long term chronic asthma sufferer who wastaking multiple medications (corticosteroids and bronchodilators). Aftertaking the composition of Example 1 A for about 10 days he reported thathis chest congestion was clearing and that he was breathing moreconfidently. He indicated that he no longer “hesitate [s] to runupstairs”.

Example 12

[0115] Two children from the same family both having long term historiesof chronic respiratory disease with asthma like symptoms and who did notobtain much benefit from using routine corticosteroids/bronchodilatorshave, subsequent to taking the composition of Example 1 B have been freeof bronchial complications. The girl aged 8 has been taking 1 capsule inthe morning and 2 capsules in the evening, and the boy aged 6 has beentaking one capsule in each of the morning and evening. Each child hasalso taken one capsule of dimethyl sulphone per day.

Example 13 In Vitro Studies

[0116] Extract Preparation

[0117] Extracts of components were prepared by stirring maceratedsamples overnight in methanol. The mixtures were centrifuged, thesupernatants drawn off and dried to remove all traces of the extractingsolvent. Resulting solids were re-suspended in normal saline (0.9% w/vNaCl) at saturated concentrations. Extract No. Ingredient Solvent 2Apocynin Methanol 5 Picrorrhiza kurroa Methanol 8 Ginko biloba Methanol

[0118] Method

[0119] Extracts 2, 5 and 8 were reconstituted in 0.9% saline atsaturated concentrations.

[0120] Citrated whole blood, from healthy volunteers, was spun at 900rpm for 20 minutes to obtain platelet rich plasma (PRP). Bornaggregometry was then carried out within 1 hour of blood being taken.Extracts 2, 5, and 8 were added to 450 μl PRP either singly (6 μl), orin combination with one other extract (3 μl each), or all the extractsin combination (2 μl each). PRP was then stimulated with ADP (Sigma)4×10⁻⁶M. 6 μ of saline was added to PRP for the control. Aggregation wasmeasured in a PAP4C aggregometer (BioData Corp. Horsham USA) over 10minutes.

[0121] The dose of agonist was chosen to give slightly sub-optimalaggregation thus showing the maximum effect of any inhibition. Doses ofextracts were chosen to show the effect on platelets when used alone andany added and/or synergistic effect of using combinations. All data isrecorded as the maximum aggregation.

[0122] Results

[0123] The results are shown in the following table (“Table Example 13”)and FIGS. 1 to 3.

[0124] In the control treatment ADP 4×10⁻⁶M produce aggregation of 78.5%(Table 1 and FIG. 1). Extract 2 (FIG. 1 + 2) aggregation in response toADP reduced by 32% compared with the control. Extract 5 (FIG. 1 + 2)aggregation was reduced by 6%. Extract 8 (FIG. 1 + 2) aggregationreduced by 29%. Extracts 2 + 5 (FIG. 1 + 3) reduced ADP inducedaggregation by 15%. Extracts 2 + 8 (FIG. 1 + 3) aggregation in responseto ADP reduced by 31%. Extracts 5 + 8 (FIG. 1 + 3) reduced the responseto ADP by 45%. Extracts 2 + 5 + 8 (FIG. 1 + 3) aggregation response toADP reduced by 43%.

[0125] Discussion

[0126] Extracts 2, 5 and 8 all reduced platelet aggregation in responseto ADP. The combination of extracts 2+5 and 2+8 also caused a reductionin the ADP induced aggregation. The combination of extracts 5+8 added toplatelets reduced aggregation in response to ADP by 45% and thecombination of extracts 2+5+8 reduced response by 35%; both these weregreater than could be predicted by the additive effect of the extractsalone. Thus, in these combinations {(5+8: Picrorrhiza and Ginko biloba)and (2+5+8: Apocynin and Picrorrhiza and Ginko biloba)} the inhibitioncaused by the extracts works in a manner that is at least greater thanthe predicted additive effect.

[0127] Leukotriene receptor antagonists are currently used and approvedin the treatment of asthma, these compounds affect the signaltransmission between platelets and immune cells. The components of thepathways associated with these receptors e.g. arachidonic acidmetabolism and PAF stimulation all appear to be inhibited by theextracts of the apocynin, Picrorrhiza kurroa and Ginko biloba mixture.

[0128] The fact that the extracts of each component affect theactivation of platelets and PMN (data not shown) differentially indicatethat the extracts affect distinct elements of a number of differentactivation pathways. They demonstrate a higher effect on PMN thanplatelets which appears to support their primary action as ananti-inflammatory mixture in asthma.

[0129] The effects of extracts on platelet aggregation show a markedinhibition of ADP induced aggregation. ADP induced aggregation iscritically dependent on cyclooxygenase enzyme activity, an enzyme classblocked by aspirin and used extensively in blood clot prevention. Theseresults provide strong support for the potential application of themixture in reducing thrombosis and cardiac related problems (for exampleischaemia and blood flow problems, arrhythmias induced by experimentalmyocardial ischaemia, prevention or reduction of arteriolar spasm andproblems caused by thrombus formation).

[0130] The fact that there are significant gastrointestinal problemsseen in the use of aspirin offers the mixture as a potential replacementfor aspirin therapy. Furthermore, it has been well documented thataspirin can induce asthma. The compositions of the invention, as well asbeing useful in treatment of asthma, may be used instead of aspirin (orNSAIDs of the aspirin type) in treating conditions such as bloodclotting in patients prone to asthma or similar conditions.

[0131] Table Example 13: Raw data showing the % aggregation in responseto ADP in the presence of extracts 2, 5 and 8 alone or in combination.ADP 4 × 10⁻⁶ M Extract % Aggregation control 78.5 2-6 μl 53.5 5-6 μl73.5 8-6 μl 55.5 2-3 μl + 5-3 μl 67 2-3 μl + 8-3 μl 54 8-3 μl + 5-3 μl43 2-2 μl + 5-2 μl + 8-2 μl 44.75

Veterinary Examples Example 14 (Dogs)

[0132] Dosage

[0133] apocynin: 10 mg—50 mg/15 kg body weight per day

[0134] ginkgo biloba: 20 mg—100 mg/15 kg body weight per day

[0135] picrorrhiza kurroa: 50 mg 100 mg/15 kg body weight per day

[0136] phosphatidyl choline: 100 mg—200 mg/15 kg body weight per day.

[0137] The regime involves a loading dose (the high figures: apocynin 50mg/15 kg body weight per day; ginkgo biloba 100 mg/15 kg body weight perday; picrorrhiza kurroa: 100 mg/15 kg body weight per day; andphosphatidyl choline: 200 mg/15 kg body weight per day) and amaintenance dose (the low figures: apocynin 10 mg/15 kg body weight perday; ginkgo biloba 20 mg/15 kg body weight per day; picrorrhiza kurroa:50 mg/15 kg body weight per day; and phosphatidyl choline: 100 mg/15 kgbody weight per day).

[0138] The loading dose is from three to ten days according toindividual perceived clinical need. After the loading dose themaintenance dose follows for a minimum (normally) of 30 days continuingas needed. The doses are scaled according for individual size/bodyweight.

[0139] The composition may be used to treat osteo-arthritic problems,hip-dysplasia and the mature (older/stiffer) dog. In acute casesalthough non steroidal anti-inflammatories (NSAIDs) are required theNSAID dose can be routinely reduced to ⅛ the recommended/advisedanti-inflammatory dose to achieve the same clinical pain relief whensupplemented additionally with the compositions embodying the invention.

Example 14A.

[0140] A Viszla (now 8 years old) with obliterative osteoarthritis (O/A)of both hind knee joints and O/A of left elbow joint. Originally (at age2) was unable to bear weight on its hind limbs. Now clinicallysound/well following treatment with the composition (much improvedwithout need of NSAIDs or other anti inflammatory medications)

Example 14B.

[0141] A Mixed Raced Dog with O/A from Age of Eight.

[0142] Now clinically sound/well following treatment with thecomposition (much improved without need of NSAIDs or other antiinflammatory medications)

Example 14C.

[0143] A Doberman with Hip Dysplasia. Sound (much improved without needof NSAIDs or other anti inflammatory medications) when taking theformulations of the invention. Unsound and unable to jump when nottaking the formulations.

Example 14D.

[0144] Labradors (several)with arthritis: sound on formulations (muchimproved without need of NSAIDs or other anti inflammatory medications)of the invention—previously unsound.

Example 14E.

[0145] Treatment of Leishmaniasis (Canine)

[0146] This is a life threatening problems that plagues theMediterranean countries. It is, at best, debilitating and requiresongoing supportive medication with a poor prognosis. A Great Dane in askeletal condition with multiple lymphadenopathies, pustular oozinglesions all over the body and 80% hair loss was presented after allconventional treatment regimes had failed. This condition is typical ofthe terminal phase of this disease. After 10 weeks of treatment with theformulations of the invention (Example 14) it was not possible todistinguish between this dog and normal healthy other members of hisrace, i.e. he was clinically normal.

Example 15 (Horses)

[0147] Dosage Horses (450 kg body weight).

[0148] apocynin: 100 mg—500 mg per day

[0149] ginkgo biloba: 2,000 mg—10,000 mg per day

[0150] picrorrhiza kurroa: 500 mg—2,500 mg per day

[0151] phosphatidyl choline: 2,000 mg—10,000 mg per day

[0152] The regime involves a loading dose (the high figures: apocynin100 mg per day; ginkgo biloba 2000 mg per day; picrorrhiza kurroa: 500mg per day; and phosphatidyl choline: 2000 mg per day) and a maintenancedose (the low figures: apocynin 500 mg per day; ginkgo biloba 10000 mgper day; picrorrhiza kurroa: 2500 mg per day; and phosphatidyl choline:10000 mg per day).

[0153] The loading dose is from three to ten days according toindividual perceived clinical need. After the loading dose themaintenance dose follows for a minimum (normally) of 30 days continuingas needed. The doses are scaled according for individual size/bodyweight. The dose was added as a powder in the animals feed.

[0154] The compositions used in the following Examples are:

[0155] JMJ (Apocynin Mixture)

[0156] 400 kg of JMJ mix comprises Apocynin (acetovanillone) 0.188 kgand 9.2 kg Picrorrhiza kurroa root.

[0157] FRS (gingko biloba mix)

[0158] 103 kg of FRS includes 5 kg ginkgo biloba.

[0159] D-Tox

[0160] Includes 1 g ginkgo biloba per 15.05 g D-Tox.

[0161] JMJ, FRA and D-Tox are available from Nutrilabs of Penrhos,Raglan, Monmouthshire. They are used to make the following Examplecompositions according to the invention, which were used in Examples Ato AA below. The following gives a daily dose for 450 kg horse. With anyof the following Example Compositions during ANY acute phase a loadingdose of 3 times the daily dose may be used to assist a rapid return to‘well being’.

Example PR

[0162] dimethyl sulphone (MSM) 2 g FRS 10 g JMJ 10 g apocynin 75 mgferulic acid 100 mg picrorrhiza kurroa 100 mg pancreas extract 100 mg

Example MG

[0163] Same as the EXAMPLE PR but includes a medicated shampoo and anMSM/Zinc based cream for local application

Example LA

[0164] Dimethyl sulphone (MSM) 2 g

[0165] FRS 15 g

[0166] JMJ 10 g

[0167] Apocynin 200 mg

[0168] picrorrhiza kurroa 250 mg

[0169] Chitin/Chitosan 1 g

[0170] Salvia militorrhiza 2 g

[0171] Thrive 6 g

[0172] The above gives a daily dose for 450 kg horse.

Example RE

[0173] dimethyl sulphone (MSM) 3 g

[0174] FRS 10 g

[0175] JMJ 10 g

[0176] apocynin 200 mg

[0177] picrorrhiza kurroa 250 mg

Example SU

[0178] MSM 2 g

[0179] FRS 10 g

[0180] JMJ 15 g

[0181] glucosamine 500 mg

[0182] apocynin 200 mg

[0183] chitin 2 g

Example D-Ty

[0184] Viburnum opulus (bark) 2 g

[0185] FRS Mix 10 g

[0186] JMJ 10 g

[0187] ferulic acid 200 mg

[0188] cimicifuga racemosa 1 g

[0189] Bynatone (11)# 5 g

Example PF

[0190] Dimethyl sulphone (MSM) 2 g

[0191] FRS 15 g

[0192] JMJ 10 g

[0193] Apocynin 200 mg

[0194] picrorrhiza kurroa 250 mg

[0195] Chitin/Chitosan 1 g

[0196] Salvia militorrhiza 2 g

[0197] Thrive (RTM) 6 g

Example DE

[0198] dimethyl sulphone (MSM) 2 g

[0199] equisetum arvense 2 g

[0200] FRS 10 g

[0201] JMJ 15 g

[0202] urtica dioica 2 g

[0203] angelica sinensis 1 g

[0204] liver extract 100 mg

[0205] salvia miltiorrhiza 1 g

[0206] rehmannia glutinosa 1 g

[0207] The following compositions and methods are within the scope ofthe invention.

[0208] A The horse is a 13 yr old Welsh Section B mare that had sufferedfrom Seasonal Pruritic Dermatitis since she was two years old. If leftuntreated she would rub herself raw. Veterinary advice was sought andbenzyl benzoate and stabling were advised. EXAMPLE PR was tried and animprovement was seen within three weeks. The mare now only rubs on veryhot days and benzyl benzoate is only used on a very limited basis. Themare is now shown to a very high level of health.

[0209] B. The horse is a three-year-old Welsh Cob. Seasonal PruriticDermatitis was seen; veterinary advice was sought and benzyl benzoatewas prescribed. EXAMPLE PR was tried and after five days the horse wasdoing very well and continues on a low maintenance level of EXAMPLE PR.The animal has been turned out over summer for the first time in twoyears, with the only other product used being a fly repellent.

[0210] C. The horse is a 16.2 h.h, 14 yr old mare that has suffered withSeasonal Pruritic Dermatitis on her stomach only during summer monthssince four years of age. She was also aggressive when that area wastouched, e.g.: when the leg was applied. Veterinary advice was soughtand many different approaches were tried but none worked. EXAMPLE PR wastried as a last resort and an improvement was seen within one tub. Themare now only rubs her stomach occasionally and seems much more content.She is easier and happier to ride.

[0211] D. The horse aged 22, had suffered from Seasonal PruriticDermatitis for many years. Veterinary advice was sought and stabling,benzyl benzoate, garlic and antihistamine injections were advised. Onadvice EXAMPLE PR was tried. An improvement was seen within one monthand hair regrowth was seen within six weeks, while antihistaminetreatments were no longer needed. The horse still rubs occasionally buthas a mane where previously it was bare, and the tail is no longerrubbed.

[0212] E. Housed at the same stable as horse D above and aged 5 hadsuffered from Seasonal Pruritic Dermatitis for many years. EXAMPLE PRwas tried. An improvement was seen within one month and hair regrowthwas seen within six weeks. Antihistamines are no longer needed.

[0213] F. The horse had suffered from bad Ecezematous Dermatitis andfilled legs when stabled every year for the past six years. Veterinaryadvice was sought and a variety of treatments was tried. The resultsvaried from improving the symptoms (Peridine shampoo) to worsening thecondition (liquid paraffin). On advice EXAMPLE MG was tried and animprovement seen within one week. There was an 80% improvement in thefilled legs, and no Ecezematous Dermatitis at all, all winter.

[0214] G. The horse is a 13.2 h.h. 10 yr old New Forest mare that hadsuffered from laminitis for four years Veterinary advice had beensought. X-rays confirmed the condition and heartbar shoes, increasedroughage in the diet, and restricted grazing were advised with onlylimited results. EXAMPLE L was used and an improvement was seen withintwo weeks. The pony is now fit and well and laminitis is not seen withEXAMPLE L being used as part of an overall management approach.

[0215] H. The horse is a 13.2 h.h, 12 year old mare who had previouslysuffered from laminitis when in foal. She was overweight when put infoal again and the laminitis recurred. Following unsuccessful treatmentsit was decided to try EXAMPLE L; an improvement was seen within two daysof commencement of treatment. Within six weeks there was no sign oflaminitis in the hoof.

[0216] I. The horse is a 14 yr old Arabian mare which suffered withchronic COPD for many years. Veterinary advice was sought andVentipulmin and steroids were tried. The mare deteriorated to the pointwhere she couldn't even walk to her field. EXAMPLE RE was tried and animprovement was seen within one day. The horse is now a happy, fitanimal. J. EXAMPLE SU treatment of a hock deformity in a mare (which hadcaused lameness and impaired action) gave an “incredible difference” inaction and soundness. Following a dressage competition localisedswelling, heat and intermittent lameness were seen in the near fore.Veterinary advice was sought. A mild strain to the check ligament wasdiagnosed; the horse was given a cortisone injection into the leg andbox rest with controlled exercise was advised. As the mare was alreadyon EXAMPLE SU it was suggested that she try D-Tox as well (i.e.treatment continued with the effective concentration of gingko bilobaincreased). Three days after starting the D-Tox course the swelling andheat had both noticeably reduced. Eleven days after starting the leg hadgone right down and all the heat had gone from it. The mare was still onbox rest but was being led out to graze for up to 1 ½ hours daily.Overall the mare received a month's course of D-Tox. Two days afterfinishing the D-Tox a flair up of slight swelling and heat was seenagain; however this disappeared over the following two days with carefulmanagement. The mare continued on EXAMPLE SU throughout the wholetreatment.

[0217] Thus, EXAMPLE SU plus D-Tox is within the scope of the invention;increase of concentration of gingko biloba may be used to manage chronicsymptoms.

[0218] K. Following a number of traumas (a bad fall on the road andsevere attack of colic), this horse developed COPD (chronic obstructivepulmonary disease) and a mite allergy at about the same time. Thedevelopment of the problems also coincided with losing summer grazingand having to rely on 1 acre of poor grazing. The neighbour to the fieldcontinually has a dung heap burning (365 days a year), the prevailingwind is over the field and the owner considers that this must contributeto the respiratory condition. The COPD made it impossible to continue incompetition and excercise. Horse K also suffered from an allergicreaction to mites in his fetlocks and heels which caused weeping,bleeding, pus and scabs. This is contributing to his reluctance to work.Ventipulmin (clenbuterol) and Dermobion (nitrofuazone, prednisolone,neomycin, chlorophyll, cod-liver oil) were prescribed by the attendingveterinary surgeon. Ventipulmin had no effect. Dermobion only worked inthe short term.. The owner reported that EXAMPLE RE had a “more lastingbeneficial effect”. D-Tox was added and the owner reported a furtherimprovement within three weeks, with full cure of the cough. Slightrespiratory sounds are still heard during fast work, but prior totreatment he was previously unable to do fast work at all; these soundsmay be due to permanent lung damage as this is a long standing condition(˜5 years) Horse. K can now go for two-hour hacks without any problem.

[0219] L. Having had the mare L for 15 years the owner had had noprevious problems with either weight or laminitis. The vet diagnosedlaminitis and prescribed Finadyne injections, followed by powder,remedial shoeing and Bute. A blood test revealed a hormonal imbalance.The mare had been on Bute for two months but reacted to it, with ulcersaround the mouth and sores on the muzzle. The owner was recommended totry D-Tox and EXAMPLE LA. An improvement was seen within a week. Thehorse is now 95% sound.

[0220] M. Despite a careful management regime the horse suffered from anacute onset of very severe laminitis; he could barely move. Veterinaryadvice was sought and Percutol ointment was tried on all eight digitalpulses, along with four sachets of Bute a day, and box rest for sixweeks. No great improvement was seen and the horse was given just 24hours, by the vet, to show an improvement before being put down. Theowner was advised to try D-Tox and EXAMPLE LA. Within twenty-four hoursof starting the D-Tox the horse had been reprieved from being put down,and within four days he was moving reasonably freely. He has now builtup to three hours grass per day and continues to improve. On one day aslight pulse was felt, and the horse was kept in with restricted dietand increased D-Tox (i.e. increased gingko biloba)and was fine againwithin twenty four hours.

[0221] N. The horse is a twelve-year-old Trakehner x Arab mare who hassuffered from occasional intermittent bouts of azoturia over the lastsix years. There seemed no particular reason for the attacks, and theyusually occurred just after exercising. Veterinary advice was sought andvitamin E and selenium were suggested; this had no effect. The mareinitially started on D-Tox which she was on for eight months beforechanging to EXAMPLE D-Ty. No incidence of tying up has been seen sincethe D-Ty was first introduced. The horse is on one scoop.(llg) of D-Tytogether with salt and a broad based vitamin and mineral provider.

[0222] O. The horse is a twenty five year old Anglo Arab who hassuffered with Ecezematous Dermatitis continually for the past fiveyears. Veterinary advice was sought and white lead lotion was advised.The owner, decided to try EXAMPLE MG and NAF Teatree Oil Shampoo. Withinthree weeks the swelling had reduced, the scabs were softening andfalling off, and the skin started to heal very quickly. Within one monththe condition had healed completely for the first time in ive years.

[0223] P. The horse is a 14.2 h.h. 12 yr old cob that has suffered fromSeasonal Pruritic Dermatitis (Sweet Itch) for a considerable time.Veterinary advice had been sought and “various lotions and potions” hadbeen prescribed; none had had any significant effect. The owner decidedto try EXAMPLE PR and saw an improvement within two weeks. There isstill a little scratching, but not as severe. There is no inflammationor bald patches and he isn't forever against a tree or fence. The ownerstopped using it for one week and noticed a reversal immediately.

[0224] Q. The horse is a 30 yr old 13 h.h pony that began to itch. Hewould rub for up to 30 minutes at a time, chew himself until bleedingand developed bald weepy patches. The flanks, chest, rump and shoulderswere affected, but not the mane or tail, and it continued throughoutwinter so Seasonal Pruritic Dermatitis was ruled out. Veterinary advicewas sought. Skin scrapings were taken, and nothing found. An“unspecified allergy” was diagnosed and medicated shampoo and steroidsprescribed. The horse's owner was keen to avoid steroids and EXAMPLE PRwas used. An improvement was seen in two days, and the owner wascompletely happy with the results within two weeks.

[0225] S. The horse is a 5 yr old 15.2 h.h gelding who had suffered fromSeasonal Pruritic Dermatitis since he was two and a half. The owner hadtried several different products but none had worked and the horse'sface, mane and tail were rubbed raw. EXAMPLE PR gave an improvementwithin a few weeks. Seasonal Pruritic Dermatitis is now well controlledwhen fed from April to late September.

[0226] T. The horse is a 16 h.h 12 yr old Anglo Arab who suffered fromSeasonal Pruritic Dermatitis and raised insect bites, first seen in thesummer 1999. EXAMPLE PR gave an improvement within four weeks ofcommenncement, and the owner was completely happy with the resultswithin six weeks. Any obvious insect bites now quickly disappear.

[0227] U. The horse is a l9 yr old 12 h.h. Welsh Section A gelding.Seasonal Pruritic Dermatitis has developed since the age of 12, althoughmildly at first he now rubs mane, tail, rump and neck until raw. EXAMPLEPR gave a 90% improvement. The owner thinks that it has been even moresuccessful when used as a preventative. With careful management thehorse now has a superb coat.

[0228] V. The horse is a 14 yr old Irish Sport Horse who had alwayssuffered from Ecezematous Dermatitis, seen particularly as scabs on hisfetlocks and swelling in his white legs. The owner tried EXAMPLE DE andnoticed an immediate reduction in the swelling. Fuderex Cream was alsoused topically once the scabs had been removed; it was observed that thescabs did not reappear. The owner continued to use EXAMPLE DE andFuderex Cream as a preventative measure throughout the risk period, andthe horse remained well and unaffected.

[0229] W. The horse is an 11 yr old Clysdale gelding who suffered withEcezematous Dermatitis every year. Veterinary advice had been sought andvarious injections, antibiotics, washes and creams were tried withlittle or no success. EXAMPLE DE gave an improvement within two weeks,despite the challenge being particularly great as the horse hasunclipped, traditional, heavy horse feathers.

[0230] X. The animal is a 10 hh 10 yr old donkey that had suffered withrain scald annually. Veterinary advice was sought and treating topicallywith Hibiscrub was prescribed. A course of antibiotics was used when theproblem worsened. The owner, was advised to try EXAMPLE DE to preventthe problem recurring. It was obvious that the challenge was stillpresent as slight scabbiness was seen in the early stages, but not asbad as previous years and it quickly cleared completely.

[0231] Y. The horse is a ten-year-old miniature Shetland who firstsuffered from a bout of laminitis in 1997. He remained clear of furtherattack until attending a show in May 1998 where he managed to graze somerich grass. From that time onwards the horse's owner, described him asalways being “just on the edge.” Veterinary advice was sought from anequine specialist who took X-rays and said that the damage was not toogreat. Electrolytes were prescribed, however they had no effect and noimprovement was seen. Treatment with EXAMPLE PF was so effective thatthe owner was “amazed by the improvement”. Within one month of startingon EXAMPLE PF the horse was better than he had been for a long time,even giving Bucking Bronco displays for the first time in years just forfun!

[0232] Z. The horse is a twenty-year-old pony that suffered his firstattack of laminitis in June 2000. Veterinary advice was sought and hewas given anti-inflammatory and pain killing injections, paste and amonths course of powder. An improvement was seen with EXAMPLE PF and theowner declared herself completely satisfied with the productsperformance within one month. The horse is now well and walks outsoundly, neither the foot nor sole are sore.

[0233] AA. The horse is a 3 yr old Shetland gelding that suffers verybadly with skin problems. In addition to Seasonal Pruritic Dermatitisduring the spring and summer he also suffers with hives, scabs, soresand poor coat condition year round. Veterinary advice was sought anddermatitis diagnosed. Dermobion and insecticidal shampoos wereprescribed but no improvement was seen. The owner had also tried many ofthe other shampoos, washes, creams and supplements available but not hadhad any effect. An improvement was seen within three weeks of startingEXAMPLE PR. The horse now has a clean coat, a 15 cm long mane and awhole tail. The coat is shiny, and the mane silkier. The horse is nolonger scratching and his temperament has also improved, presumably dueto him no longer being irritated.

Example 16 Example RE Plus

[0234] For treatment of Horses at 450 kg body weight 20 grams per day. ALoading dose for a period of up to ten days of 100 g/d may be requiredEach 20.2 g of Example RE includes: MSM (dimethyl sulfone) 3 gAcetovanillone (apocynin) 1 g Phosphatidyl choline (lecithin) 0.5 gGinkgo biloba (leaf) 2 g Ginkgo biloba (standardised extract: 22% ginkgoflavone glycosides) 0.1 g Picrorrhiza kurroa 1 g the balance beingherbal extracts and vitamins.

[0235] It will be appreciated that other compositions are within thescope of the invention.

1. A composition comprising (a) a Platelet Activating Factor (PAF)Inhibitor and (b) an antioxidant which interferes with the arachidonicacid cascade.
 2. A composition according to claim 1 wherein the PlateletActivating Factor (PAF) Inhibitor (a) is a gingkolide.
 3. A compositionaccording to claim 2 wherein the gingkolide comprises gingko biloba, oran extract or component thereof.
 4. A composition according to any ofclaims 1 to 3 wherein the antioxidant (b) is an NADPH oxide inhibitor.5. A composition according to any of claims 1 to 3 wherein theantioxidant (b) increases glutathione synthesis.
 6. A compositionaccording to any of claims 1 to 4 wherein antioxidant (b) is aneutrophil oxidative burst antagonist.
 7. A composition according to anypreceding claim wherein the antioxidant (b) is apocynin.
 8. Acomposition according to claim 7 wherein the apocynin is in isolatedform.
 9. A composition according to any preceding claim which furthercomprises apocynin in natural form.
 10. A composition according to claim9 wherein the apocynin in natural form is in the form of one or more ofpicrorrhiza kurroa, apocynum cannabinium, apocynum venatum apocynumandrosaemifolium.
 11. A composition according to any preceding claimwhich further comprises a surfactant.
 12. A composition according to anypreceding claim which further comprises dimethyl sulfone.
 13. Acomposition according to any preceding claim comprising gingko bilobaand apocynin; wherein the ratio by mass of gingko biloba: apocynin isbetween about 3:10 and about 3.4:1.
 14. A composition according to claim13 wherein the ratio by mass of gingko biloba: apocynin is between about1:1 and about 3:1.
 15. A pharmaceutical preparation comprising acomposition according to any preceding claim.
 16. A pharmaceuticalpreparation according to claim 15 for the treatment or the relief ofinflammatory disease, thrombosis, cardiac problems, and/or conditionscaused by platelet induced blood clotting.
 17. A pharmaceuticalpreparation according to claim 15 or claim 16 for the treatment or therelief of inflammatory respiratory disease
 18. A veterinary preparationcomprising a composition according to any of claims 1 to
 14. 19. Aveterinary preparation according to claim 18 for the treatment or therelief of inflammatory disease, thrombosis, cardiac problems, and/orconditions caused by platelet induced blood clotting, in a non humananimal.
 20. A pharmaceutical composition comprising (a) a PlateletActivating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade.
 21. A pharmaceuticalcomposition according to claim 20 wherein the Platelet Activating Factor(PAF) Inhibitor (a) is a gingkolide.
 22. A pharmaceutical compositionaccording to claim 21 wherein the gingkolide comprises gingko biloba, oran extract or component thereof.
 23. A pharmaceutical compositionaccording to any of claims 20 to 22 wherein the antioxidant (b) is anNADPH oxide inhibitor.
 24. A pharmaceutical composition according to anyof claims 20 to 22 wherein the antioxidant (b) increases glutathionesynthesis.
 25. A pharmaceutical composition according to any of claims20 to 23 wherein antioxidant (b) is a is a neutrophil oxidative burstantagonist.
 26. A pharmaceutical composition according to any of claims20 to 25 wherein the antioxidant (b) is apocynin.
 27. A pharmaceuticalcomposition according to claim 26 wherein the apocynin is in isolatedform.
 28. A pharmaceutical composition according to any of claims 20 to27 which further comprises apocynin in natural form.
 29. Apharmaceutical composition according to claim 28 wherein the apocynin innatural form is in the form of one or more of picrorrhiza kurroa,apocynum cannabinium, apocynin venatum and apocynum androsaemifolium.30. A pharmaceutical composition according to any of claims 20 to 29which further comprises a surfactant.
 31. A pharmaceutical compositionaccording to any of claims 20 to 30 which further comprises dimethylsulfone.
 32. A pharmaceutical composition according to any of claims 20to 31 according to any preceding claim comprising gingko biloba andapocynin; wherein the ratio by mass of gingko biloba: apocynin isbetween about 3:10 and about 60:1.
 32. A pharmaceutical compositionaccording to claim 32 wherein the ratio by mass of gingko biloba:apocynin is between about 6:1 and about 0.4:1.
 33. An orally activepharmaceutical preparation for the treatment of inflammatory respiratorydisease comprising (a) a Platelet Activating Factor (PAF) Inhibitor and(b) an antioxidant which interferes with the arachidonic acid cascade.34. An orally active pharmaceutical preparation according to claim 33for the treatment of asthma.
 35. A method of treatment or prevention ofinflammatory disease, thrombosis, cardiac problems, and/or conditionscaused by platelet induced blood clotting, in human or other animalsubject comprising the step(s) of administering to the subject (a) aPlatelet Activating Factor (PAF) Inhibitor and (b) an antioxidant whichinterferes with the arachidonic acid cascade.
 36. A method according toclaim 35 in which the the Platelet Activating Factor (PAF) Inhibitor isa gingko biloba.
 37. A method according to claim 36 in which gingkobiloba is administered to a human at a daily dose of between 1 mg/kgbodyweight and 25 mg/kg body weight (standardised to gingko flavoneglycosides 24%).
 38. A method according to any of claims 35 to 37 inwhich the antioxidant (b) is apocynin.
 39. A method according to claims38 in which the apocynin is administered to a human at a daily dose ofbetween 60 μkg/kg body weight and 20 mg/kg body weight.
 40. A methodaccording to any of claims 35 to 39 which further comprises the step ofadministering a natural form of antioxidant (b).
 41. A kit of parts fora preparation for treatment or prevention of inflamatory disease,thrombosis, cardiac problems, and/or conditions caused by plateletinduced blood clotting in human or other animal subject comprising atleast one dose of (a) a Platelet Activating Factor (PAF) Inhibitor and(b) at least one dose of an antioxidant which interferes with thearachidonic acid cascade.
 42. A method of dose sparing a therapeuticagent comprising the step of administering to the patient a preparationcomprising (a) a Platelet Activating Factor (PAF) Inhibitor and (b) anantioxidant which interferes with the arachidonic acid cascade.
 43. Apharmaceutical composition comprising a unitary dose of gingko bilobaequivalent to between 1 mg/kg bodyweight and 25 mg/kg body weight gingkobiloba(standardised to gingko flavone glycosides 24%) and a unitary doseof apocynin of between 60μg/kg body weight and 20 mg/kg body weight. 44.A composition including apocynin, picorrhiza kurroa (standardised toKutkin min 2%, or equivalent); lactoferrin; ginkgo biloba(standardisedto gingko flavone glycosides 18%, or equivalent); bee pollen; chlorellapyrenoidosa; phophatidylcholine; and fucus vesiculosus in the ratio(parts by weight)100:200:60:150:120:250:100:20.
 45. A compositionincluding apocynin, picorrhiza kurroa (standardised to Kutkin min 2%, orequivalent); ginkgo biloba(standardised to gingko flavone glycosides24%, or equivalent); chlorella pyrenoidosa; and phophatidylcholine inthe ratio (parts by weight)180:360:260:100:100.
 47. A compositionincluding apocynin, picorrhiza kurroa (standardised to Kutkin min 2%, orequivalent); lactoferrin; ginkgo biloba(standardised to gingko flavoneglycosides 24%, or equivalent); bee pollen; chlorella pyrenoidosa;phophatidylcholine; and fucus vesiculosus in the ratio (parts byweight)100:200:150:100:280:150:20.
 50. A composition as hereinbeforedescribed with reference to any of Example 1, 1A, 1B, Example 14,Example 14 and/or Example 16.